Men and women respond differently to cocaine. Although epidemiological data show that more men than women abuse cocaine, there is preclinical and clinical evidence indicating that females are more vulnerable to its psychostimulant effects. Evidence also indicates that estrogen is at least partly responsible for this difference in sensitivity. Most studies point to the striatum and nucleus accumbens (NAcc) as brain areas on which estrogen acts to produce this gender difference. However, one area that has received little attention as potentially important for mediating this effect is the medial preoptic area (MPOA). The MPOA is sexually dimorphic, it is involved in regulating naturally rewarding behaviors, and it is one of the most sensitive regions to estrogen activity. These attributes make the MPOA a likely candidate in which estrogen might act to mediate gender-sensitive differences in response to cocaine. However, little is known about its role in this effect. The goals of these studies is: (1) to determine whether cocaine-induced activation of the medial preoptic nucleus (MPN) is sexually dimorphic, and whether it is mediated by estrogen;(2) to determine whether estrogen works via the MPOA to mediate cocaine-induced DA activity in the NAcc;(3) to determine whether estrogen acts via the MPOA to mediate cocaine-induced conditioned place preference, as a measure of cocaine's rewarding effects. Using neuroanatomical, neurochemical, and behavioral assays, the proposed work will examine whether estrogen enhances female1s response to cocaine via the MPOA. The planned experiments will also contribute to a more complete understanding of how hypothalamic mechanisms, especially one that is highly sensitive to gonadal signals, may affect response to cocaine use. Finally, the proposed studies will help us better understand the neuroendocrine regulation of gender-sensitive differences in response to cocaine, by exploring a possible new mechanism mediating this effect. Such an understanding may be beneficial when designing treatments for addiction, when gender-sensitive differences are especially important. PUBLIC HEALTH RELAVANCE The proposed studies will help us better understand the neuroendocrine regulation of gender-sensitive differences in response to cocaine, by exploring a possible new mechanism mediating this effect. Such an understanding may be beneficial when designing treatments for addiction, when gender-sensitive differences are especially important.